U.S. patent application number 10/928431 was filed with the patent office on 2005-02-17 for bioresorbable hydrogel compositions for implantable prostheses.
This patent application is currently assigned to SCIMED LIFE SYSTEMS, INC.. Invention is credited to Lentz, D. Christian, Loomis, Gary L..
Application Number | 20050038134 10/928431 |
Document ID | / |
Family ID | 46256670 |
Filed Date | 2005-02-17 |
United States Patent
Application |
20050038134 |
Kind Code |
A1 |
Loomis, Gary L. ; et
al. |
February 17, 2005 |
Bioresorbable hydrogel compositions for implantable prostheses
Abstract
Crosslinked compositions formed from water-insoluble copolymers
are disclosed. These compositions are copolymers having a
bioresorbable region, a hydrophilic region and at least two
cross-linkable functional groups per polymer chain. Crosslinking of
these polymers can be effected in solution in organic solvents or
in solvent-free systems. If crosslinking occurs in a humid
environment, a hydrogel will form. If crosslinking occurs in a
non-humid environment, a xerogel will form which will form a
hydrogel when exposed to a humid environment and the resulting
crosslinked materials form hydrogels when exposed to humid
environments. These hydrogels are useful as components in medical
devices such as implantable prostheses. In addition, such hydrogels
are useful as delivery vehicles for therapeutic agents and as
scaffolding for tissue engineering applications.
Inventors: |
Loomis, Gary L.;
(Morristown, NJ) ; Lentz, D. Christian; (Pompton
Plains, NJ) |
Correspondence
Address: |
HOFFMANN & BARON, LLP
6900 JERICHO TURNPIKE
SYOSSET
NY
11791
US
|
Assignee: |
SCIMED LIFE SYSTEMS, INC.
|
Family ID: |
46256670 |
Appl. No.: |
10/928431 |
Filed: |
August 27, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10928431 |
Aug 27, 2004 |
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10683500 |
Oct 10, 2003 |
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10683500 |
Oct 10, 2003 |
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10369777 |
Feb 19, 2003 |
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6660827 |
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10369777 |
Feb 19, 2003 |
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09957427 |
Sep 20, 2001 |
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6534560 |
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09957427 |
Sep 20, 2001 |
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09395725 |
Sep 14, 1999 |
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6316522 |
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09395725 |
Sep 14, 1999 |
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09243379 |
Feb 1, 1999 |
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6028164 |
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09243379 |
Feb 1, 1999 |
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09145588 |
Sep 2, 1998 |
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6005020 |
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09145588 |
Sep 2, 1998 |
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08914130 |
Aug 18, 1997 |
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5854382 |
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Current U.S.
Class: |
523/113 |
Current CPC
Class: |
A61L 27/54 20130101;
A61L 2300/606 20130101; A61L 2300/416 20130101; A61L 27/34
20130101; C08G 63/676 20130101; A61L 31/16 20130101; C08G 63/664
20130101; A61L 27/52 20130101; A61L 29/16 20130101; C08G 64/183
20130101; A61L 2300/42 20130101; A61L 2300/41 20130101; A61L 27/58
20130101; C08L 67/00 20130101; A61L 2300/602 20130101; A61L 31/148
20130101; A61L 31/10 20130101; A61L 31/06 20130101; A61L 27/34
20130101; A61L 2300/236 20130101; A61L 2300/408 20130101; A61L
2300/406 20130101; A61K 9/204 20130101; A61L 2300/254 20130101;
A61L 2300/00 20130101; A61L 2300/604 20130101; A61K 9/2027
20130101 |
Class at
Publication: |
523/113 |
International
Class: |
C08L 001/00 |
Claims
What is claimed is:
1. A medical device having at least one surface coated with a
bioresorbable coating composition; said coating composition
comprising a water-insoluble copolymer comprising (1) a
bioresorbable region; (2) a hydrophilic region; and (3) a plurality
of cross-linkable functional groups per polymer chain.
2. The medical device of claim 1, wherein said medical device is a
member selected from the group consisting of conduits, vascular
grafts, textile materials, and polymeric films;
3. The medical device of claim 1, wherein said medical device
comprises a polymer selected from the group consisting of olefin
polymers, polyethylene, polypropylene, polyvinyl chloride,
polytetrafluoroethylene, fluorinated ethylene propylene copolymer,
polyvinyl acetate, polystyrene, poly(ethylene terephthalate),
polyurethane, polyurea, silicone rubbers, polyamides,
polycarbonates, polyaldehydes, natural rubbers, polyester
copolymer, styrene-butadiene copolymers, and combinations
thereof.
4. The medical device of claim 1, wherein the medical device is a
polytetrafluoroethylene vascular graft.
5. The medical device of claim 4, wherein said vascular graft has a
luminal and an external surface; and said coating composition is in
contact with said luminal surface.
6. The medical device of claim 5, wherein said coating composition
includes at least one drug or bio-active agent.
7. The medical device of claim 6, wherein said drug or bio-active
agent is dispersed throughout said coating composition.
8. The medical device of claim 6, wherein said coating composition
provides a controlled release of the drug or bio-active agent.
9. The medical device of claim 8, wherein said drug or bio-active
agent is selected from the group consisting of heparin, heparin
sulfate, hirudin, chondroitin sulfate, dermatan sulfate, keratin
sulfate, lytic agents, urokinase, streptokinase, penicillin,
cephalosporins, vancomycins, aminoglycosides, quinolones,
polymyxins, erythromycins, tetracyclines, chloramphenicols,
clindamycins, lincomycins, sulfonamides, paclitaxel, docetaxel,
alkylating agents, mechlorethamine, chlorambucil, cyclophosphamide,
melphalan, ifosfamide, antimetabolites, methotrexate,
6-mercaptopurine, 5-fluorouracil, cytarabine, plant alkaloids,
vinblastine, vincristine, etoposide, doxorubicin, daunomycin,
bleomycin, mitomycin, nitrosureas, carmustine, lomustine,
cisplatin, interferon, enzymes, asparaginase, tamoxifen, flutamide,
amantadines, rimantadines, ribavirins, idoxuridines, vidarabines,
trifluridines, acyclovirs, ganciclovirs, zidovudines, foscarnets,
and combinations thereof.
10. A medical device comprising a vascular graft having at least
one surface coated with a coating composition; said coating
composition comprising a water-insoluble copolymer comprising (1) a
bioresorbable region; (2) a hydrophilic region; and (3) a plurality
of cross-linkable functional groups per polymer chain, and at least
one drug or bioactive agent; said coating composition providing a
controlled release of said drug or bioactive agent.
11. The medical device of claim 10, wherein said medical device
comprises a polymer selected from the group consisting of olefin
polymers, polyethylene, polypropylene, polyvinyl chloride,
polytetrafluoroethylene, fluorinated ethylene propylene copolymer,
polyvinyl acetate, polystyrene, poly(ethylene terephthalate),
polyurethane, polyurea, silicone rubbers, polyamides,
polycarbonates, polyaldehydes, natural rubbers, polyester
copolymer, styrene-butadiene copolymers, and combinations
thereof.
12. The medical device of claim 10, wherein said vascular graft has
a luminal and an external surface; and said coating composition is
in contact with said luminal surface.
13. A drug eluting vascular graft for the controlled and sustained
delivery of at least one therapeutic agent within the internal
lumen of the vascular graft.
14. The drug eluting vascular graft of claim 13, wherein said
vascular graft may be comprised of expanded polytetrafluoroethylene
(ePTFE), polyvinyl chloride polypropylene, fluorinated ethylene
propylene, polyetherurethaneurea, or other biocompatible
plastics.
15. The drug eluting vascular graft of claim 13, wherein said
vascular graft may be of various diameters and lengths.
16. The drug eluting vascular graft of claim 13, wherein at least
one polymer is polyester.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/683,500, filed Oct. 10, 2003, which is a continuation of
U.S. application Ser. No. 10/369,777, filed on Feb. 19, 2003, which
is a continuation of U.S. application Ser. No. 09/957,427, filed on
Sep. 20, 2001, now U.S. Pat. No. 6,534,560, which is a continuation
of Ser. No. 09/395,725, filed on Sep. 14, 1999, now U.S. Pat. No.
6,316,522, which is continuation-in-part of application Ser. No.
09/243,379, filed on Feb. 1, 1999, now U.S. Pat. No. 6,028,164,
which is a continuation of application Ser. No. 09/145,588, filed
on Sep. 2, 1998, now U.S. Pat. No. 6,005,020, which is divisional
of Ser. No. 08/914,130, filed on Aug. 18, 1997, now U.S. Pat. No.
5,854,382, all of which are herein incorporated by reference.
FIELD OF INVENTION
[0002] This invention relates generally to compositions useful as
components of medical devices. Particularly, the present invention
relates to cross-linkable compositions formed from a
water-insoluble copolymer having a bioresorbable region, a
hydrophilic region and at least two cross-linkable functional
groups per polymer chain. More particularly, this invention relates
to such compositions comprising an organic solution. When
crosslinked and exposed to a humid environment, these compositions
form bioresorbable hydrogels. Furthermore, these compositions are
useful as delivery vehicles for therapeutic agents. Processes for
forming such hydrogels are also disclosed, as are processes for
forming medical devices having such hydrogels incorporated
therein.
BACKGROUND OF RELATED TECHNOLOGY
[0003] It is generally known to provide a porous material, such as
an implantable prosthesis, with a biocompatible biodegradable
sealant or coating composition which initially renders the porous
material substantially fluid-impermeable. Over time, such a sealant
composition is resorbed and the healing process naturally takes
over the sealing function as tissue ingrowth encapsulates the
prosthesis. Naturally derived, as well as chemically synthesized,
sealant compositions are well-known.
[0004] An example of a medical device having a sealing means is
described at column 4, lines 38-55 of U.S. Pat. No. 5,843,160. Such
sealing means preclude the egress of blood and prevent endoluminal
leakage. A specific example of a sealing ring or sleeve is set
forth at column 11, lines 10-36.
[0005] Natural materials, such as collagen and gelatin, have been
widely used on textile grafts. U.S. Pat. Nos. 4,842,575 and
5,034,265 to Hoffman Jr., et al. disclose the use of collagen as a
sealant composition for grafts. More recently, co-owned and
co-pending U.S. Ser. No. 08/713,801 discloses the use of a hydrogel
or sol-gel mixture of polysaccharides for rendering fluid-tight
porous implantable devices. Such sealant compositions are
beneficial in that they are able to seal an implantable device
without the need for chemical modification of the surface thereof
and provide improved bioresorbability as the healing process
occurs. Furthermore, fibrin, an insoluble protein formed during the
blood clotting process, has also been used as a sealant for porous
implantable devices.
[0006] The use of such biologically-derived sealant compositions,
however, suffers from several drawbacks. One such drawback is the
difficulty in producing consistent coatings due to variations
inherent in natural materials. Another drawback is that the body
might identify such compositions as foreign and mount an immune
response thereto. Thus, biologically-based sealant compositions can
cause inflammation, as well as infection, at or around the site of
implantation. This might lead to life-threatening
complications.
[0007] Accordingly, attempts have been made to design sealant
systems from chemically synthesized materials which are easy to
manufacture, which are easy to control the desired characteristics
and qualities thereof, and which have less potential for causing
adverse biological reactions. For example, U.S. Pat. No. 4,826,945
to Cohn et al. discloses synthetically-produced resorbable block
copolymers of poly(.alpha.-hydroxy-carboxylic
acid)/poly(oxyalkylene) which are used to make absorbable sutures,
wound and burn dressings, and partially or totally biodegradable
vascular grafts. However, these copolymers are not crosslinked. The
poly(alkylene) segments of such bio-absorbable copolymers are
disclosed to be water-soluble so that the body can excrete the
degraded block copolymer compositions. See also, Younes, H. and
Cohn, D., J. Biomed. Mater. Res. 21, 1301-1316 (1987) and Cohn, D.
and Younes, H., J. Biomed. Mater. Res. 22, 993-1009 (1988). As set
forth above, these compositions are not crosslinked and, as a
consequence, are relatively quickly bio-absorbed. Moreover, these
non-crosslinked compositions generally require the presence of
crystalline segments to retain their structural integrity. As a
result of such crystalline segments, these compositions have
limited utility as sealants for vascular grafts.
[0008] Furthermore, U.S. Pat. No. 4,438,253 to Casey et al.
discloses tri-block copolymers produced from the
transesterification of poly(glycolic acid) and a hydroxyl-ended
poly(alkylene glycol). Such compositions are disclosed for use as
resorbable monofilament sutures. The flexibility of such
compositions is controlled by the incorporation of an aromatic
orthocarbonate, such as tetra-p-tolyl orthocarbonate, into the
copolymer structure. The strength and flexibility which makes such
a composition useful as a suture, however, does not necessarily
make it appropriate for use as a sealant for a porous implantable
prosthesis. Moreover, these tri-block copolymers are substantially
non-crosslinked. Thus, while these compositions are somewhat
hydrophilic, they do not form hydrogels.
[0009] Accordingly, attempts have been made to engineer
bio-compatible hydrogel compositions whose integrity can be
controlled through crosslinking. For example, U.S. Pat. Nos.
5,410,016 and 5,529,914 to Hubbell et al. disclose water-soluble
systems which, when crosslinked, utilize block copolymers having a
water-soluble central block segment sandwiched between two
hydrolytically labile extensions. Such copolymers are further
end-capped with photopolymerizable acrylate functionalities. When
crosslinked, these systems become hydrogels. The water soluble
central block of copolymers can include poly(ethylene glycol),
whereas the hydrolytically labile extensions can be a
poly(.alpha.-hydroxy acid), such as polyglycolic acid or polylactic
acid. See, Sawhney, A. S., Pathak, C. P., Hubbell, J. A.,
Macromolecules 1993, 26, 581-587. See also, U.S. Pat. No.
5,854,382, disclosing an aqueous emulsion of water-insoluble
copolymer which is crosslinked to form a hydrogel.
[0010] Furthermore, U.S. Pat. No. 5,202,413 to Spinu discloses
biodegradable multi-block copolymers having sequentially ordered
blocks of polylactide and/or polyglycolide produced by ring-opening
polymerization of lactide and/or glycolide onto either an
oligomeric diol or a diamine residue followed by chain extension
with a di-functional compound, such as diisocyanate,
diacylchloride, or dichlorosilane. The general structure of such a
composition is R-(A-B-A-L).sub.x-A-B-A-R, where A is a polyhydroxy
acid, such as polylactide, polyglycolide or a copolymer thereof, B
is an oligomeric diol or diamine residue, L is a diacyl residue
derived from an aromatic diacyl halide or diisocyanate, and R is H
or an end-capping group, such as an acyl radical. A major
difference between the compositions set forth in the Spinu '413
patent and those described by the Cohn references supra is that
Spinu uses lactide blocks whereas Cohn uses lactic acid blocks.
Furthermore, like the Cohn copolymers, the copolymers described in
the Spinu '413 patent are not cross-linkable.
[0011] In general, all of the synthetic compositions set forth
above describe copolymers having one or more segments which are
water-soluble. Accordingly, many of the compositions described by
these references are intended to be rapidly biodegraded by the
body.
[0012] Thus, there is a need for water-insoluble, fully
cross-linkable polymeric materials which are easily synthesized and
provide controlled bioresorption in vivo. Moreover, there is a need
for improved, cost-efficient, synthetic sealant compositions for
porous, implantable prostheses which are characterized by their
ability to self-emulsify and form stable, low viscosity emulsions.
There is a further need for sealant compositions which are quickly
cured, exist as hydrogels in an aqueous environment, and which
remain flexible while dehydrated without the need for an external
plasticizer. The present invention is directed to meeting these and
other needs.
SUMMARY OF THE INVENTION
[0013] In one aspect of the present invention, there is provided a
process for forming a covalently crosslinked composition in an
organic solvent. This composition includes a water-insoluble
copolymer which has a bioresorbable region, a hydrophilic region,
and a plurality of cross-linkable functional groups per polymer
chain. Use of an organic solution allows for a broader range of
bioresorbable compositions to be used in the present invention than
is possible where a substantially inorganic solvent alone is used.
Individual uses for these compositions are as polymeric substrates,
as scaffolding for tissue engineering, or as therapeutic agent
delivery systems.
[0014] In another aspect of the present invention, there is
provided a medical device which has, as at least one component
thereof, a bioresorbable composition. This composition comprises a
hydrogel formed from the crosslinking of a polymer containing a
bioresorbable region, a hydrophilic region, a plurality of
cross-linkable functional groups, and, optionally, a crosslinking
agent, in an organic solution.
[0015] In a further aspect of the present invention, there is
provided a process for forming a hydrogel. This process comprises
providing a solution of a water-insoluble copolymer in an organic
solvent. The water-insoluble copolymer includes a bioresorbable
region, a hydrophilic region, a plurality of cross-linkable
functional groups per polymer chain, and, optionally, a
crosslinking agent. Crosslinking of the copolymer results in
formation of a xerogel. This xerogel will form a hydrogel when
exposed to a humid environment.
[0016] In a further aspect of the present invention there is
provided another process for forming a hydrogel. This process
comprises providing a solution of the above-mentioned
water-insoluble copolymer in a solvent mixture comprised of a
water-miscible organic solvent and water. Effecting a crosslinking
reaction of the copolymer composition in this solution directly
forms the hydrogel.
[0017] In yet a further aspect of the present invention, there is
provided a process for forming a device, particularly a medical
device, coated with a hydrogel. The hydrogel is formed from an
organic solution which comprises a water-insoluble copolymer having
a bioresorbable region, a hydrophilic region, a plurality of
cross-linkable functional groups per polymer chain and, optionally,
a crosslinking agent. This process comprises applying the solution
to the medical device, initiating a crosslinking reaction,
subsequently removing the organic solvent, and exposing the
resulting xerogel to a humid environment to form a hydrogel.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The present invention is directed to covalently crosslinked
compositions formed from water-insoluble copolymers. The copolymers
of the present invention include a bioresorbable region, a
hydrophilic region, and a plurality of cross-linkable functional
groups per polymer chain, and are present in an organic solution.
Prior to being crosslinked, the water-insoluble copolymer
compositions are soluble in organic solvents or solvent mixtures
containing water-miscible organic solvents and water. Once
crosslinked, such compositions form xerogels (dry gels) in the
absence of water, or hydrogels in the presence of water. For
purposes of the present invention, xerogels are crosslinked
compositions which, when exposed to a humid environment, form
hydrogels. Hydrogels (also known as aquagels) are materials that
are able to swell rapidly in excess water and retail large volumes
of water in their swollen structures. Hydrogels do not dissolve in
water and maintain three-dimensional networks. They are usually
made of hydrophilic polymer molecules which are crosslinked either
by chemical bonds or by other cohesion forces such as ionic
interaction, hydrogen bonding, or hydrophobic interaction.
Hydrogels are elastic solids in the sense that there exists a
remembered reference configuration to which the system returns even
after being deformed for a very long time. (see Park et al,
Biodegradable Hydrogels for Drug Delivery, Technomic Pub. Co., July
1993). These definitions are provided for reference only, and are
not meant in any way to limit the materials to which these terms
might apply. Xerogels or hydrogels formed from the compositions of
the present invention can be introduced to a porous material to
form a medical device.
[0019] Compositions of the present invention might also function as
delivery vehicles for therapeutic agents. The use of organic
solvents permits the rapid formation of various compositions
containing water-insoluble additives and other water-insoluble
polymers. The use of organic solvents makes it easier to
incorporate certain pharmaceutical substances, as these substances
are generally soluble in organic solvents. Additionally, organic
solvents are easy to eliminate in the manufacturing process,
simplifying the process of producing the compositions of the
present invention, as well as the process of producing medical
devices associated with hydrogels formed by the present invention.
Further, organic solvents permit faster crosslinking of the polymer
than will occur in the absence of organic solvents, and the use of
organic solvents avoids the quenching of free radicals by water.
Most additives, including other polymers, will be soluble in
organic solvents, thereby facilitating their inclusion in
compositions of the present invention.
[0020] The copolymers of the compositions of the present invention
are multi-block copolymers including, for example, di-block
copolymers, tri-block copolymers, star copolymers, and the like.
For purposes of illustration only, a typical tri-block copolymer of
the present invention may have the following general formula:
xABAx (I)
[0021] wherein A is the bioresorbable region, B is the hydrophilic
region and x is the cross-linkable functional group.
[0022] A specific example of a copolymer useful in the composition
of the present invention has the following chemical structure:
1
[0023] wherein x is from about 10 to about 100 and y is from about
50 to about 500, so long as the composition remains substantially
water-insoluble as a whole.
[0024] A more specific example of a copolymer useful in the
composition of the present invention has the following chemical
structure: 2
[0025] wherein the ratio of A to B is about 3:1, x is from about 10
to about 100, and y is from about 50 to about 300, so long as the
composition remains substantially water-insoluble as a whole.
[0026] One feature of the present invention is that the
cross-linkable copolymer composition is substantially
water-insoluble. For purposes of the present invention,
"water-insoluble" is intended to mean that the copolymers of the
present invention have water solubility in the range of about 0.0
gm/100 ml to about 0.5 gm/100 ml. A method for determining the
water-solubility of copolymers of the present invention is set
forth below in Example 5.
[0027] As set forth above, the water-insoluble copolymer of the
composition of the present invention includes a bioresorbable
region. For purposes of the present invention, the term
"bioresorbable" means that this region is capable of being
metabolized or broken down and resorbed and/or eliminated through
normal excretory routes in the body. Such metabolites or break-down
products should be substantially non-toxic to the body.
[0028] The bioresorbable region can be hydrophobic. In another
aspect, the bioresorbable region can be designed to be hydrophilic
so long as the copolymer composition as a whole remains
substantially water-insoluble. The relative proportions or ratios
of the bioresorbable to the hydrophilic regions, respectively, as
well as any functional groups contained therein, are specifically
selected to render the copolymer composition substantially
water-insoluble. Furthermore, when crosslinked, these compositions
are sufficiently hydrophilic to form hydrogels in aqueous
environments. Such hydrogels, as set forth in more detail below,
can form a fluid-impermeable barrier when applied to a porous
material, particularly a medical device. The specific ratio of the
two regions of the block copolymer composition of the present
invention will, of course, vary depending upon the intended
application and will be affected by the desired physical properties
of the resulting hydrogels, the site of implantation, and other
factors. For example, the composition of the present invention
remains substantially water-insoluble when the ratio of the
hydrophilic region to the hydrophobic region to is from about 5:1
to about 1:5, on a weight basis. Additionally, the selected ratios
will depend on the relative hydrophilicity and molecular weights of
the biodegradable and hydrophilic compounds chosen.
[0029] The bioresorbable region of the copolymer used in a
composition of the present invention can be designed to be
hydrolytically and/or enzymatically cleavable. For purposes of the
present invention, "hydrolytically cleavable" refers to the
susceptibility of the copolymer, particularly the bioresorbable
region, to hydrolysis in water or in a water-containing
environment. Similarly, "enzymatically cleavable", as used herein,
refers to the susceptibility of the copolymer, particularly the
bioresorbable region, to cleavage by endogenous or exogenous
enzymes.
[0030] Based on the characteristics set forth above, a number of
different compounds can comprise the bioresorbable region. The
bioresorbable region can include, without limitation, for example,
poly(esters), poly(hydroxy acids), poly(lactones), poly(amides),
poly(ester-amides), poly(amino acids), poly(anhydrides),
poly(ortho-esters), poly(carbonates), poly(phosphazines),
poly(thioesters), polysaccharides and mixtures thereof.
Furthermore, the bioresorbable region can also include, for
example, a poly(hydroxy) acid including poly(.alpha.-hydroxy) acids
and poly(.beta.-hydroxy) acids. Such poly(hydroxy) acids include,
for example, polylactic acid, polyglycolic acid, polycaproic acid,
polybutyric acid, polyvaleric acid, and copolymers and mixtures
thereof.
[0031] The substantially water-insoluble copolymers of the present
invention form solutions in organic solvents and in solvent
mixtures containing water-miscible organic solvents and minor
amounts of water. For the purposes of the present invention, an
organic solution of the copolymer is defined as the copolymer in an
organic solvent or the copolymer in a mixture of an organic solvent
and up to about 50% water. Organic solvents which can be used, for
example, are ethanol, 1-propanol, butanol, diethyl ether,
dichloromethane, chloroform, dimethyl formamide, dimethyl
acetamide, hexamethylphosphoramide, and toluene. These solvents are
exemplary only and are not meant to be limit in any manner the
solvents which may be used in the present invention. Another aspect
of the present invention utilizes the copolymer in a liquid state
without solvent.
[0032] As set forth above, the copolymer of the composition of the
present invention also includes a hydrophilic region. For purposes
of the present invention, "hydrophilic" is used in the traditional
sense of a material or substance having an affinity for water.
Although the copolymer contains a hydrophilic region, this region
is designed and/or selected so that the copolymer composition, as a
whole, remains substantially water-insoluble at all times.
[0033] When placed in vivo, the hydrophilic region can be processed
into excretable and/or metabolizable fragments. Thus, the
hydrophilic region can comprise, without limitation, for example,
polyethers, polyalkylene oxides, poly(vinyl pyrrolidine),
poly(vinyl alcohol), poly(alkyl oxazolines), polysaccharides,
polypeptides, proteins, and copolymers and mixtures thereof.
Furthermore, the hydrophilic region can also be, for example, a
poly(alkylene) oxide. Such poly(alkylene) oxides can include, for
example, poly(ethylene) oxide, poly(propylene) oxide, and mixtures
and copolymers thereof.
[0034] As set forth above, the composition of the present invention
also includes a plurality of cross-linkable functional groups. Any
cross-linkable functional group can be included in the copolymer so
long as the copolymer which includes the cross-linkable functional
group is capable of forming a hydrogel. Cross-linkable functional
groups which can be used in the present invention include
olefinically unsaturated groups. Suitable olefinically unsaturated
functional groups are, without limitation, for example, acrylates,
methacrylates, butenoates, maleates, allyl ethers, allyl
thioesters, and N-allyl carbamates.
[0035] The cross-linkable functional groups may be present at any
point along the polymer chain of the present composition, so long
as their location does not interfere with the intended function
thereof, as set forth above. Furthermore, the cross-linkable
functional groups may be present in the polymer chain of the
present invention in numbers greater than two, so long as the
intended function of the present composition is not
compromised.
[0036] Preferably, at least two olefinically unsaturated functional
groups are present on the polymer chain of the present composition.
As set forth above, the number of olefinically unsaturated
functional groups present on the polymer chain may be more than
two, depending upon the particular application of the composition.
Although the olefinically unsaturated functional groups may be
positioned anywhere on the polymer chain of the present
composition, it is preferred that at least one olefinically
unsaturated functional group be positioned at a terminus of the
polymer chain. More preferably, an olefinically unsaturated group
is positioned at both terminal ends of the polymer chain.
Furthermore, as there are at least two functional groups present in
the copolymer composition, the functional groups contained therein
may be the same or different.
[0037] Crosslinking of the polymer compositions of the present
invention is accomplished through the cross-linkable functional
groups. These functional groups can be activated by a variety of
crosslinking means in order to crosslink the copolymer composition.
These crosslinking means may include, for example, high energy
radiation, thermal radiation, visible light, and combinations
thereof. The composition of the present invention can also include
free radical initiators. Such free radical initiators can include,
for example, a peroxide or an azo compound. Preferably, a
crosslinking agent used in the present invention is a free radical
initiator, such-as, for example, 2,2'-Azobis
(N,N'dimethyleneisobutyramidine) dihydrochloride or benzoyl
peroxide.
[0038] In the present invention, the composition is crosslinked in
an organic medium, as set forth above. Furthermore, once
crosslinked, the copolymer composition is able to form a hydrogel
upon exposure to a humid environment. As set forth above, such
hydrogels are polymeric materials that swell in water without
dissolving and that retain a significant amount of water in their
structures while maintaining dimensional stability. Such
compositions have properties intermediate between those of liquids
and solids. Hydrogels also deform elastically and recover, yet may
flow at higher stresses. Hydrogel compositions of the present
invention are less transient and can be controlled more easily than
known non-crosslinked sealant compositions, as set forth
previously. Thus, compositions of the present invention have
distinct advantages over known compositions and have superior
functionality as sealants for, as an example, porous materials,
particularly implantable medical devices, and as delivery devices
for, as an example, therapeutic agents.
[0039] In one aspect of the invention, a therapeutic agent, such
as, for example, a drug or bio-active agent, can be introduced into
the copolymer composition of the present invention. The drug or
bio-active agent will be released in a controlled manner as the
composition is bioresorbed. Thus, compositions of the present
invention can be used to deliver therapeutic agents to specific
sites in the body. Furthermore, such compositions can be engineered
to bioresorb at particular rates by selecting the ratios of the
bioresorbable regions to the hydrophilic regions as well as by
controlling the degree of crosslinking and the molecular weight
thereof. Thus, the present compositions are able to deliver
controlled quantities of a therapeutic agent to a specific site in
the body as the hydrogel is bioresorbed.
[0040] Any drug or bio-active agent can be incorporated into a
composition of the present invention provided that it does not
interfere with the required characteristics and functions of the
composition. Examples of suitable drugs or bio-active agents
include, for example, without limitation, thrombo-resistant agents,
antibiotic agents, anti-tumor agents, anti-viral agents,
anti-angiogenic agents, angiogenic agents, anti-inflammatory
agents, cell cycle regulating agents, their homologs, derivatives,
fragments, pharmaceutical salts and combinations thereof.
[0041] Useful thrombo-resistant agents can include, for example,
heparin, heparin sulfate, hirudin, chondroitin sulfate, dermatan
sulfate, keratin sulfate, lytic agents, including urokinase and
streptokinase, their homologs, analogs, fragments, derivatives and
pharmaceutical salts thereof.
[0042] Useful antibiotics can include, for example, penicillins,
cephalosporins, vancomycins, aminoglycosides, quinolones,
polymyxins, erythromycins, tetracyclines, chloramphenicols,
clindamycins, lincomycins, sulfonamides, their homologs, analogs,
fragments, derivatives, pharmaceutical salts and mixtures
thereof.
[0043] Useful anti-tumor agents can include, for example,
paclitaxel, docetaxel, alkylating agents including mechlorethamine,
chlorambucil, cyclophosphamide, melphalan and ifosfamide;
antimetabolites including methotrexate, 6-mercaptopurine,
5-fluorouracil and cytarabine; plant alkaloids including
vinblastine, vincristine and etoposide; antibiotics including
doxorubicin, daunomycin, bleomycin, and mitomycin; nitrosureas
including carmustine and lomustine; inorganic ions including
cisplatin; biological response modifiers including interferon;
enzymes including asparaginase; and hormones including tamoxifen
and flutamide; their homologs, analogs, fragments, derivatives,
pharmaceutical salts and mixtures thereof.
[0044] Useful anti-viral agents can include, for example,
amantadines, rimantadines, ribavirins, idoxuridines, vidarabines,
trifluridines, acyclovirs, ganciclovirs, zidovudines, foscarnets,
interferons, their homologs, analogs, fragments, derivatives,
pharmaceutical salts and mixtures thereof.
[0045] In another aspect of the present invention, there is
provided a medical device having associated with at least one
surface thereof a bioresorbable coating composition of the present
invention. This coating composition includes a hydrogel which is
formed from the crosslinking of a polymer containing a
bioresorbable region, a hydrophilic region, a plurality of
crosslinked functional groups, and, optionally, a crosslinking
agent, as set forth previously.
[0046] In particular, the present bioresorbable coating
compositions are intended to coat medical devices made from
implantable materials. These bioresorbable coatings are capable of
rendering porous medical devices, such as conduits, vascular
grafts, textile materials, polymeric films, and the like,
substantially impermeable to fluid. For purposes of the present
invention, "substantially impermeable to fluid" refers to the
specific porosity of a material, such as a porous vascular or
endovascular graft. Porosity of textile materials is often measured
with a Wesolowski Porosity tester. With this apparatus, a graft is
tied off at one end and the free end is attached to a valve on a
porometer so that the graft hangs freely in a vertical position.
Then, water is run through the graft for one minute and the water
that escapes from the graft is collected and measured. The specific
porosity of the graft is then calculated according to the following
formula: 1 P = V A
[0047] where V is the volume of water collected in ml/min and A is
the surface area of the graft exposed to water in cm.sup.2. A
specific porosity of <1.0 ml/min/cm.sup.2 is considered an
acceptable amount of leakage for an implantable vascular graft.
Accordingly, for purposes of this invention, a substantially
fluid-impermeable graft is defined as a graft with a specific
porosity, after impregnation with a sealant of the present
invention, of <1.0 ml/min/cm.sup.2. Porosities meeting and
exceeding the acceptable specific porosity criteria set forth above
can be achieved through the use of certain block copolymers
described herein having polyether-polyester segments.
[0048] Implantable materials which can be used in the present
invention can include, for example, polymeric materials,
non-polymeric materials, and combinations thereof. The polymeric
materials can include, for example, olefin polymers, including
polyethylene, polypropylene, polyvinyl chloride,
polytetrafluoroethylene, fluorinated ethylene propylene copolymer,
polyvinyl acetate, polystyrene, poly(ethylene terephthalate),
polyurethane, polyurea, silicone rubbers, polyamides,
polycarbonates, polyaldehydes, natural rubbers, polyester
copolymers, styrene-butadiene copolymers and combinations thereof.
Non-polymeric implantable materials can include, for example,
ceramics, metals, inorganic glasses, pyrolytic carbon and
combinations thereof. The implantable materials set forth above are
intended to be exemplary only and should not be construed in any
way to limit the types of materials which may be used in the
present invention.
[0049] As set forth above, the implantable materials may be used in
the present invention can be used to manufacture medical devices,
such as for example, endoprostheses. Grafts, stents and combination
graft-stent devices are contemplated. Preferably, these medical
devices are vascular or endovascular grafts. Useful vascular or
endovascular grafts include those which are knitted, braided or
woven, and can have velour or double velour surfaces.
Alternatively, the medical device can be manufactured from an
extruded polymer, such as polytetrafluoroethylene (PTFE),
particularly expanded polytetrafluoroethylene (ePTFE), polyethylene
terephthalate (PET), fluorinated ethylene propylene copolymer
(FEP), polyurethane, silicone and the like. Composite structures
are also contemplated.
[0050] In another preferred aspect, a medical device of the present
invention can be a catheter, a guidewire, a trocar, an introducer
sheath, or the like. When coated onto such devices, the composition
of the present invention imparts increased bio-compatibility to one
or more surfaces thereof. Furthermore, when the composition of the
present invention includes a drug or bio-active agent, specific
therapeutic effects can be imparted to the surfaces of such
devices. Moreover, the hydrophilic region of the polymer
composition of the present invention can impart increased
lubriciousness to the surfaces of, for example, a guidewire or
other similar device.
[0051] Thus, any medical device to which the bioresorbable coating
composition of the present invention can adhere may be used for
purposes of the present invention. Accordingly, the examples of
implantable materials and medical devices set forth above are for
purposes of illustration only and are not intended to limit the
scope of the materials and devices to which the present
bioresorbable coatings can be applied or otherwise associated
therewith.
[0052] In another aspect of the present invention, pre-crosslinked
and post-crosslinked polymers of the present invention can be used
in tissue engineering applications as supports for cells.
Appropriate tissue scaffolding structures are known in the art,
such as the prosthetic articular cartilage described in U.S. Pat.
No. 5,306,311, the porous biodegradable scaffolding described in WO
94/25079, and the prevascularized implants described in WO 93/08850
(all hereby incorporated by reference herein). Methods of seeding
and/or culturing cells in tissue scaffoldings are also known in the
art, such as those methods disclosed in EPO 422 209 B1, WO
88/03785, WO 90/12604, and WO 95/33821 (all hereby incorporated by
reference herein). Additionally, the cross-linkable prepolymers of
the present invention can be used to encapsulate cells for tissue
engineering purposes.
[0053] In another aspect of the present invention, there is
provided a process for forming a hydrogel. This process includes:
(1) providing an organic solution of a water-insoluble copolymer
which contains a bioresorbable region, a hydrophilic region, a
plurality of cross-linkable functional groups per polymer chain,
and, optionally, a crosslinking agent, and (2) effecting a
crosslinking reaction, as set forth previously, and (3) exposing
the composition to a humid environment to form a hydrogel, where
steps (2) and (3) do not have to be carried out in any particular
order. In this process, the cross-linkable functional groups can
be, but are not limited to, olefinically unsaturated groups. As set
forth previously, the crosslinking agent can be a free radical
initiator, such as an azo or a peroxide compound. Still further,
the crosslinking reaction can be, for example, thermally or
photochemically affected. The hydrogel is formed when the copolymer
composition is exposed to a humid environment.
[0054] In yet another aspect of the present invention, there is
provided a process for forming a medical device coated with a
hydrogel. The hydrogel may be formed by a process as set forth
above. The polymer composition may be introduced into the medical
device and subsequently crosslinked. Alternatively, the polymer
composition may be crosslinked prior to being introduced into the
medical device. Once crosslinked, the polymer composition may form
a hydrogel when exposed to a humid environment.
[0055] The crosslinking agent can be activated in both humid and
non-humid environments. In some instances, it is preferred that the
activation take place in a humid environment. In these cases, the
hydrogel is formed directly. Preferably, the humid environment
contains from about 20% to about 100% water. More preferably, the
humid environment contains from about 60% to about 100% water. In
cases where the crosslinking is effected in non-humid environments,
the hydrogel is formed upon subsequent exposure of the crosslinked
copolymer to a humid environment.
[0056] The hydrogels formed by the above process can be packaged
and stored in a variety of ways. For example, the hydrogel can be
maintained in a hydrated state for an extended period of time.
Alternatively, the hydrogel can be dehydrated and stored in an
essentially desiccated state until use, since the hydration and
dehydration of these crosslinked copolymers is completely
reversible. Furthermore, plasticizers can be added to the
dehydrated materials to provide materials with increased
flexibility. Plasticizers useful in this application include, but
are not limited to, glycerol, propylene glycol, and triethyl
citrate.
[0057] Certain copolymer compositions of the present invention are
liquids and can be crosslinked in the absence of any solvent. When
this solvent-free process is employed, the hydrogel is formed upon
subsequent exposure of the crosslinked copolymer to an aqueous
environment.
[0058] The following examples are set forth to illustrate the
copolymer compositions of the present invention. These examples are
provided for the purpose of illustration only and are not intended
to be limiting in any sense.
EXAMPLE 1
Synthesis of lac-[peo/ppo]-lac Copolymer
[0059] Preparation of (Polymer A) according to the present
invention was synthesized as follows:
[0060] 100.46 gm poly(ethylene-glycol)-co-poly(propylene
glycol)-co-poly(ethylene glycol) (75 wt % ethylene glycol,
Mn=12,000) was charged to a 500 ml 4-neck reaction flask equipped
with a Dean-Stark water trap, a water-cooled condenser, a
thermometer, and a gas inlet/outlet system which allowed for the
controlled flow of nitrogen. While maintaining a nitrogen
atmosphere, 230 ml of anhydrous toluene was added to the flask, the
mixture was heated, and reflux was maintained for approximately 1
hour. During this period, any water present was collected in the
Dean-Stark water separator (approximately 30 ml of the original
toluene was also removed during this azeotropic water removal). The
flask was allowed to cool to room temperature and 45.5 gm
D,L-lactide was added to the flask along with 605 mg zinc lactate
(monohydrate) catalyst. The reaction mixture was heated to reflux
for 16, hours during which time an additional 30 ml of toluene and
was removed via the Dean-Stark water separator. 4.00 gm of
triethylamine was added to the reaction mixture at room
temperature, and, after 5 minutes of stirring, 3.34 gm of acryloyl
chloride was slowly added to the flask. The mixture was then
stirred at room temperature for 5.0 hours. Approximately 110 mg of
4-methoxy phenol was added to the flask as a free-radical
inhibitor. The solution was then transferred to large centrifuge
bottles and solid by-products were removed via centrifugation at
5.degree. C.@9000 rpm followed by decantation of the clear
supernatant solution. This solution was then reduced in vacuuo on a
rotary evaporator at 60.degree. C.@<25 mm Hg until all traces of
solvent and other volatile materials were removed. The polymer thus
prepared and isolated was a water-insoluble, viscous liquid at room
temperature.
EXAMPLE 2
Synthesis of lac-[peo/ppo]-lac Copolymer
[0061] Preparation of (Polymer B) according to the present
invention was synthesized as follows:
[0062] 100.46 gm poly(ethylene-glycol)-co-poly(propylene
glycol)-co-poly(ethylene glycol) (75 wt % ethylene glycol,
Mn=12,000) was charged to a 500 ml 4-neck reaction flask equipped
with a Dean-Stark water trap, a water-cooled condenser, a
thermometer, and a gas inlet/outlet system, which allowed for the
controlled flow of nitrogen. While maintaining a nitrogen
atmosphere, 230 ml of anhydrous toluene was added to the flask, the
mixture was heated to reflux, and reflux was maintained for
approximately 1 hour. During this period, any water present was
collected in the Dean-Stark water separator (approximately 30 ml of
the original toluene was also removed during this azeotropic water
removal). The flask was allowed to cool to room temperature and
71.44 gm D,L-lactide was added to the flask along with 605 mg zinc
lactate (monohydrate) catalyst. The reaction mixture was heated to
reflux for 16 hours, during which time an additional 30 ml of
toluene and was removed via the Dean-Stark water separator. 4.00 gm
of triethylamine was added to the reaction mixture at room
temperature, and, after 5 minutes of stirring, 3.34 gm of acryloyl
chloride was slowly added to the flask. The mixture was then
stirred at room temperature for 5.0 hours. Approximately 110 mg of
4-methoxy phenol was added to the flask as a free-radical
inhibitor. The solution was transferred to large centrifuge bottles
and solid by-products were removed via centrifugation at 5.degree.
C.@9000 rpm followed by decantation of the clear supernatant
solution. This solution was then reduced in vacuuo on a rotary
evaporator at 60.degree. C.@<25 mm Hg to remove all solvent and
other volatile materials. The polymer thus prepared and isolated
was a water-insoluble, viscous liquid at room temperature.
EXAMPLE 3
Synthesis of lac-[peo/ppo]-lac Copolymer
[0063] Preparation of (Polymer C) according to the present
invention was synthesized as follows:
[0064] 96.65 gm poly(ethylene-glycol)-co-poly(propylene
glycol)-co-poly(ethylene glycol) (75 wt % ethylene glycol,
Mn=12,000) was charged to a 500 ml 4-neck reaction flask equipped
with a Dean-Stark water trap, a water-cooled condenser, a
thermometer, and a gas inlet/outlet system which allowed for the
controlled flow of nitrogen. While maintaining a nitrogen
atmosphere, 230 ml of anhydrous toluene was added to the flask, the
mixture was heated to reflux, and reflux was maintained for
approximately 1 hour. During this period, any water present was
collected in the Dean-Stark water separator (approximately 30 ml of
the original toluene was also removed during this azeotropic water
removal). The flask was allowed to cool to room temperature and
54.71 gm D,L-lactide was added to the flask along with 605 mg zinc
lactate (monohydrate) catalyst. The reaction mixture was heated to
reflux for 16 hours, during which time an additional 30 ml of
toluene and was removed via the Dean-Stark water separator. 4.00 gm
of triethylamine was added to the reaction mixture at room
temperature, and, after 5 minutes of stirring, 3.34 gm of acryloyl
chloride was slowly added to the flask. The mixture was then
stirred at room temperature for 5.0 hours. Approximately 110 mg of
4-methoxy phenol was added to the flask as a free-radical
inhibitor. The solution was transferred to large centrifuge bottles
and solid by-products were removed via centrifugation at 5.degree.
C.@9000 rpm followed by decantation of the clear supernatant
solution. This solution was then reduced in vacuuo on a rotary
evaporator at 60.degree. C.@<25 mm Hg to remove all solvent and
other volatile materials. The polymer thus prepared and isolated
was a water-insoluble, viscous liquid at room temperature.
EXAMPLE 4
Crosslinking of the Above Polymers in an Organic Solvent or an
Organic/Aqueous Solvent System and Physical Characterization of the
Resulting Materials
[0065] Preparation and testing of crosslinked polymer systems.
[0066] Each of the solutions described below was transferred to a
shallow Teflon.TM. mold (9.0 cm.times.9.0 cm.times.1.0 cm) and
sparged with argon to remove oxygen from the solution. The filled
molds were then sealed with glass cover plates and heated in an
oven for the duration and temperatures described below.
[0067] Solution 1 (Composition D)
[0068] To a solution of 15 wt % polymer A (prepared in Example 1)
in 75:25 1-propanol/water was added Vazo 044.TM. initiator (20
mg/1.00 gm polymer). Solution was cured in a mold as described
above for 6 hours at 75.degree. C.
[0069] Solution 2 (Composition E)
[0070] To a solution of 30 wt % polymer C (prepared in Example 3)
in anhydrous 1-propanol was added benzoyl peroxide (60 mg/100 gm
polymer). Solution was cured in a mold as described above for 4
hours at 60.degree. C.
[0071] Solution 3 (Composition F)
[0072] To a solution of 15 wt % of Polymer C (prepared in Example
3) in 50:50 1-propanol/water was added 2,2'-Azobis
(N,N'-dimethyeneisobutyramid- ine) dihydrochloride [Vazo-44.TM.],
(40 mg/1.00 gm polymer). Solution was cured in a mold as described
above for 4 hours at 60.degree. C.
[0073] The resulting crosslinked compositions D, E and F were
de-molded, washed three times in deionized water and three times in
1-propanol, and dried in vacuuo to afford small sheets of
crosslinked polymer compositions. The compositions D, E and F thus
obtained were flexible at room temperature and exhibited good
elastic recovery when deformed. When exposed to aqueous
environments, the compositions D, E and F absorbed water rapidly to
afford dimensionally stable hydrogels.
[0074] Dumbbell-shaped tensile test specimens (length=38 mm, width
at center=5 mm, width at ends=16 mm) were die cut from the above
composition and stress-strain properties were determined on an
Instron.TM. tensile tester using a uniaxial pull with a cross-head
speed of 8.0 in/min and a distance of 1.0 in between grips. Results
of this testing is shown in Table 1.
1TABLE 1 Tensile Strength Elongation at Break Composition
(lb/in.sup.2) (%) D 242 1474 E 199 1270 F 270 1557
EXAMPLE 5
Procedure for Determination of Water-Solubility of Polymers
[0075] In a large centrifuge bottle, 2.0.+-.0.2 gm of polymer was
dispersed in 200.0.+-.5.0 ml of distilled water by manual agitation
for 20 minutes followed by 5 minutes of agitation in an ultrasonic
bath, all at room temperature. This dispersion was then centrifuged
at 9,000 rpm for 30 minutes, resulting in a clean separation onto
an upper polymer phase and a lower polymer phase. A 125 ml aliquot
of this upper aqueous layer was carefully removed via aspiration so
as not to disturb the lower polymer phase. This 125 ml aliquot was
lyophilized to afford a small quantity of extracted material. The %
water-solubility of the polymer was calculated as follows:
[0076] % solubility in water=(weight of extracted material/original
weight of polymer).times.100 or
[0077] solubility (grams/100 ml)=(weight of extracted material in
grams).times.(100 ml/l 25 ml).
[0078] As measured according to this procedure, the polymers of the
examples presented have water solubility in the range of 0.012 to
0.058 gm/100 ml.
[0079] The invention being thus described, it will be obvious that
the same may be varied in many ways. Such variations are not to be
regarded as a departure from the spirit and scope of the invention
and all such modifications are intended to be included within the
scope of the following claims.
* * * * *